Prominent role of PM10 but not of circulating inflammation in the link between air pollution and the risk of neurodegenerative disorders

Background Several studies revealed an implication of air pollution in neurodegenerative disorders, although this link and the potential underlying mechanisms remain unclear. Objectives To analyze the impact of air pollution on neurodegenerative risk by testing multiple pollutants simultaneously, along with other potential risk/protective factors, and the role of circulating inflammation. Methods In the Moli-sani cohort (N=24,325; ≥35 years; 51.9% women, baseline 2005-2010), we estimated yearly levels of exposure to nitrogen oxides, ozone, particulate matter (PM10), sulfur dioxide and BTX hydrocarbons in 2006-2018, applying residence geo-localization of participants and Kriging interpolation algorithm to land measurements of air pollutants. We performed a principal component (PC) analysis of pollutant levels and tested associations of the resulting PC scores with the incident risk of dementia (AD) and Parkinson's disease/parkinsonism (PD), through multivariable Cox PH regressions adjusted for age, sex, education level, and several professional and lifestyle exposures. Moreover, we tested whether a composite biomarker of circulating inflammation (INFLA-score) may explain part of these associations. Results Over 24,308 subjects with pollution data available (51.9% women, mean age 55.8(12.0) years), we extracted three PCs explaining ≥5% of pollution exposure variance: PC1 (38.2%, tagging PM10), PC2 (19.5%, O3/CO/SO2), PC3 (8.5%, NOx/BTX hydrocarbons). Over a median (IQR) follow-up of 11.2(2.0) years, we observed statistically significant associations of PC1 with an increased risk of both AD (HR[CI] = 1.06[1.04-1.08]; 218 cases) and PD (1.05[1.03-1.06]; 405 incident cases), independent on other covariates. These associations were confirmed testing average PM10 levels during follow-up time (25[19-31]% and 19[15-24]% increase of AD and PD risk, per 1 μg/m3 of PM10). INFLA-score explained a negligible (<1%) proportion of these associations. Discussion Air pollution - especially PM10 - is associated with increased neurodegenerative risk in the Italian population, independent on concurring risk factors, suggesting its reduction as a potential public health target. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The enrollment phase of the Moli-sani Study was supported by unrestricted research grants from the Pfizer Foundation (Rome, Italy), the Italian Ministry of University and Research (MIUR, Rome, Italy)-Programma Triennale di Ricerca, Decreto no.1588, and Instrumentation Laboratory, Milan, Italy. The follow-up phase of the Moli-sani Study (assessment of incident cases) was partially supported the Italian Ministry of Health (PI GdG, CoPI SC; grant no. RF-2018-12367074). The collection and elaboration of environmental data was supported by the Italian Ministry of Economic Development (PLATONE project, bando "Agenda Digitale" PON I&C 2014-2020; Prog. n. F/080032/01-03/X35). The present analyses were partially supported by the INAIL-Bric 2019 ID 47 project (Italian National Institute for Insurance against Accidents at Work; call 2019, project CUP code: F24I19000630008). No funder had a role in study design, collection, analysis, interpretation of data, writing of the manuscript, and decision to submit this article for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Moli-sani Study was approved by the ethical committee of the Catholic University of Rome (approval nr: P99, A-931/03-138-04/CE/2004, 11 February 2004) and all the participants provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors